TIL Therapy in Combination With Checkpoint Inhibitors for Metastatic Ovarian Cancer

Phase 1

Completed

Conditions: Metastatic Ovarian Cancer

Interventions: Drug: Cyclophosphamide
Drug: Fludarabine
Biological: TIL infusion
Drug: Interleukin-2
Drug: Ipilimumab
Drug: Nivolumab

Registration Number: NCT03287674

Lead Sponsor: Inge Marie Svane

Brief Summary: Adoptive T cell therapy (ACT) with tumor infiltrating lymphocytes (TIL) has achieved impressive clinical results with durable complete responses in patients with metastatic melanoma. Recently, the investigators have completed a pilot study treating 6 patients with metastatic ovarian cancer. The TILs are isolated from patients own tumor tissue followed by in vitro expansion and activation for around 4-6 weeks. Before TIL infusion the patients receive 1 week of preconditioning chemotherapy with cyclophosphamide and fludarabine. After TIL infusion Interleukin-2 is administered to support T cell activation and proliferation in vivo.

The investigators recent pilot study has shown TIL therapy in patients with metastatic ovarian cancer to be feasible and tolerable. Mainly transient clinical responses where observed and therefore the investigators plan to combine TIL therapy with checkpoint inhibitors to potentially increase the clinical effect.

Detailed Description: Adoptive T cell therapy (ACT) with tumor infiltrating lymphocytes (TIL) has achieved impressive clinical results with durable complete responses in patients with metastatic melanoma. Recently, the investigators have completed a pilot study treating 6 patients with metastatic ovarian cancer. The TILs are isolated from patients own tumor tissue followed by in vitro expansion and activation for around 4-6 weeks. Before TIL infusion the patients receive 1 week of preconditioning chemotherapy with cyclophosphamide and fludarabine. After TIL infusion Interleukin-2 is administered to support T cell activation and proliferation in vivo.

The investigators recent pilot study has shown TIL therapy in patients with metastatic ovarian cancer to be feasible and tolerable. Mainly transient clinical responses where observed and therefore the investigators plan to combine TIL therapy with checkpoint inhibitors to potentially increase the clinical effect.

Objectives:

To evaluate safety and feasibility when treating patients with metastatic ovarian cancer with ACT with TILs in combination with checkpoint inhibitors.

To evaluate treatment related immune responses To evaluate clinical efficacy

Design:

Patients will be screened with a physical exam, medical history, blood samples and ECG.

Patients will be treated with one dose of Ipilimumab 14 days before undergoing surgery to harvest tumor material for TIL production. Patients is admitted on day -8 in order to undergo lymphodepleting chemotherapy with cyclophosphamide and fludara starting day -7. On day -2 patients will start treatment with Nivolumab every 2 weeks for a total of 4 doses to increase the activity of the infused TIL product.

On day 0 patients receive TIL infusion and shortly after starts IL-2 stimulation with a daily subcutaneous dose for a total of 14 days.The patients will followed until progression or up to 5 years.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 7

Inclusion Criteria

Histological proven advanced ovarian-, fallopian tube or primary peritoneal cancer with the possibility of surgical removal of tumor tissue of > 1 cm3.
Progressive or recurrent resistant disease after platin-based chemotherapy (platinum resistant) or progressive or recurrent disease after second line or additional chemotherapy.
Age: 18 - 70 years.
ECOG performance status of ≤1 (Appendix 2).
Life expectancy of > 6 months.
At least one measurable parameter in accordance with RECIST 1.1 -criteria's.
No significant toxicities or side effects from previous treatments, except sensoric- and motoric neuropathy and/or alopecia
Sufficient renal, hepatic and hematological function
Men and women in the fertile age must use effective contraception. This applies from inclusion and until 6 months after treatment.
Able to comprehend the information given and willing to sign informed consent

Exclusion Criteria

Other malignancies, unless followed for ≥ 5 years with no sign of disease
Known hypersensitivity to one of the active drugs or one or more of the excipients.
Severe medical or psychiatric conditions
Creatinine clearance < 70 ml/min. In selected cases it can be decided to include a patient with a GFR < 70 ml/min with the use of a reduced dose of chemotherapy.
Acute/chronic infection with HIV, hepatitis, syphilis among others.
Severe allergies or previous anaphylactic reactions.
Active autoimmune disease
Pregnant women and women breastfeeding.
Need for immunosuppressive treatment e.g. corticosteroids or methotrexate. In selected cases a systemic dose of ≤10 mg prednisolone or a transient planned treatment that can be stopped before TIL therapy can be tolerated.
Simultaneous treatment with other experimental drugs.
Simultaneous treatment with other systemic anti-cancer treatments.
Patients with active and uncontrollable hypercalcaemia.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Patient group	Interleukin-2	All patients receive the same treatment. All patients are treated with one dose of Ipilimumab 14 days prior to surgical removal of tumor tissue for TIL expansion. Hospitalization for TIL treatment is approximately 3 weeks. The patients are admitted to hospital on day -8 and receive lymphodepleting chemotherapy (cyclophosphamide and fludarabine= on day -7 to day -1. The first of 4 doses of Nivolumab is administered on day -2 and every 2 weeks for at total of 4 doses. The TILs are infused on day 0 and Interleukin-2 therapy is administered on day 0 to day 13. Interleukin-2 is administered as a daily low-dose subcutaneous injection for a total for 14 days.
Patient group	TIL infusion	All patients receive the same treatment. All patients are treated with one dose of Ipilimumab 14 days prior to surgical removal of tumor tissue for TIL expansion. Hospitalization for TIL treatment is approximately 3 weeks. The patients are admitted to hospital on day -8 and receive lymphodepleting chemotherapy (cyclophosphamide and fludarabine= on day -7 to day -1. The first of 4 doses of Nivolumab is administered on day -2 and every 2 weeks for at total of 4 doses. The TILs are infused on day 0 and Interleukin-2 therapy is administered on day 0 to day 13. Interleukin-2 is administered as a daily low-dose subcutaneous injection for a total for 14 days.
Patient group	Cyclophosphamide	All patients receive the same treatment. All patients are treated with one dose of Ipilimumab 14 days prior to surgical removal of tumor tissue for TIL expansion. Hospitalization for TIL treatment is approximately 3 weeks. The patients are admitted to hospital on day -8 and receive lymphodepleting chemotherapy (cyclophosphamide and fludarabine= on day -7 to day -1. The first of 4 doses of Nivolumab is administered on day -2 and every 2 weeks for at total of 4 doses. The TILs are infused on day 0 and Interleukin-2 therapy is administered on day 0 to day 13. Interleukin-2 is administered as a daily low-dose subcutaneous injection for a total for 14 days.
Patient group	Fludarabine	All patients receive the same treatment. All patients are treated with one dose of Ipilimumab 14 days prior to surgical removal of tumor tissue for TIL expansion. Hospitalization for TIL treatment is approximately 3 weeks. The patients are admitted to hospital on day -8 and receive lymphodepleting chemotherapy (cyclophosphamide and fludarabine= on day -7 to day -1. The first of 4 doses of Nivolumab is administered on day -2 and every 2 weeks for at total of 4 doses. The TILs are infused on day 0 and Interleukin-2 therapy is administered on day 0 to day 13. Interleukin-2 is administered as a daily low-dose subcutaneous injection for a total for 14 days.
Patient group	Ipilimumab	All patients receive the same treatment. All patients are treated with one dose of Ipilimumab 14 days prior to surgical removal of tumor tissue for TIL expansion. Hospitalization for TIL treatment is approximately 3 weeks. The patients are admitted to hospital on day -8 and receive lymphodepleting chemotherapy (cyclophosphamide and fludarabine= on day -7 to day -1. The first of 4 doses of Nivolumab is administered on day -2 and every 2 weeks for at total of 4 doses. The TILs are infused on day 0 and Interleukin-2 therapy is administered on day 0 to day 13. Interleukin-2 is administered as a daily low-dose subcutaneous injection for a total for 14 days.
Patient group	Nivolumab	All patients receive the same treatment. All patients are treated with one dose of Ipilimumab 14 days prior to surgical removal of tumor tissue for TIL expansion. Hospitalization for TIL treatment is approximately 3 weeks. The patients are admitted to hospital on day -8 and receive lymphodepleting chemotherapy (cyclophosphamide and fludarabine= on day -7 to day -1. The first of 4 doses of Nivolumab is administered on day -2 and every 2 weeks for at total of 4 doses. The TILs are infused on day 0 and Interleukin-2 therapy is administered on day 0 to day 13. Interleukin-2 is administered as a daily low-dose subcutaneous injection for a total for 14 days.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Reported Adverse Events by Type	Up to 12 months	Determine the safety of TIL therapy in combination with checkpoint inhibitors for patients with ovarian-, fallopian tube or primary peritoneal cancer by reporting adverse events according to CTCAE v. 4.0.

Secondary Outcome Measures

Name	Time	Method
Objective Response Rate	Assessed up to 12 months after therapy.	Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CAT scan: Complete Response (CR) Disappearance of all target lesions (sum of all taget lesions=0) Partial Response (PR) \>=30% decrease (vs baseline) of sum of all target lesions dimension Progressive Disease (PD) new lesions or \>=20% increase (vs smallest sum of target lesions or nadir) Stable Disease (SD) when sum of all target lesions does not qualify for CR/PR/PD
Treatment Related Immune Responses	Until protocol end, until 6 months after TIL infusion	Ex vivo anti-tumor reactivity of expanded TILs after co-culture measured with flow cytometry.
Overall Survival	Up to 3 years after TIL infusion	Overall Survival (OS), defined as time from TIL infusion to death
Progression Free Survival	Up to 12 months after TIL infusion	Progression free survival (PFS): Time from TIL infusion to disease progression, relapse or death due to any cause, which ever comes first, will be used as an event.